Nitric Oxide Regulates Metaplasia in Response to Helicobacter pylori in Mice and Humans

Chronic infection with the bacterium Helicobacter pylori (HP) in humans or mice can cause atrophy of acid-secreting parietal cells (PCs) in the gastric epithelium, which leads to a series of downstream events that increase risk for development of gastric cancer. We have shown that the epithelium responds to PC atrophy by two distinct mechanisms: 1) the normal, constitutively active stem cell in the isthmus region (near the surface of the stomach) increases proliferation and 2) the post-mitotic, mature digestive-enzyme secreting chief cells in the base first dedifferentiate to a progenitor state and then also begin to proliferate in a process known as pseudopyloric metaplasia. How PC atrophy induces those responses in other cells has not been elucidated. Here we show that, both in mouse models of PC atrophy and in HP-infected human tissue, injured (but not yet apoptotic) PCs rapidly increase expression of the inducible nitric oxide synthase (iNOS) to generate nitric oxide (NO). Inhibition of iNOS in mice with an inhibitor Aminoguanylate or by using iNOS-/- mice results in less proliferation and metaplasia following PC atrophy induction. Conversely, exogenous NO from a donor such as S-Nitroso-N-acetyl-DL-penicillamine is sufficient to increase gastric unit proliferation even in uninjured mice. Once PC atrophy is extensive in mice and in humans, iNOS-expressing macrophages infiltrate the tissue. Accordingly, depletion of macrophages with clodronate liposomes also blocks the epithelial injury response. Our results implicate NO, first from PCs, then from macrophages, as a critical mediator of the pro-proliferative response of the epithelium to HP infection.